LAUSR

Carfilzomib is an irreversible epoxyketone-based proteasome inhibitor (PI) that is specific for the chymotrypsin-like active site of 20S proteasome. In 2012, carfilzomib was first approved for the treatment of relapsed/refractory multiple myeloma (MM). It has equal or higher efficacy than bortezomib. Haematological adverse events (AEs) remain the most common Grade 3–4 AEs associated with carfilzomib. Besides, carfilzomib is well-known for its unique set of cardiovascular AEs. Infection is a frequent non-haematological AE in patients with MM treated with PIs. However, definitive data on carfilzomib are still lacking. Hence, we undertook a systematic review and meta-analysis of randomised controlled trials (RCTs) to determine the relative risk of serious infections with carfilzomib in patients with MM. A comprehensive electronic search (search strategy in Appendix S1) was conducted in the MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials and Clinical Trial.gov databases to the 20 March 2019. All identified citations were uploaded in Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). Two investigators (S.W. and T.R.B.) independently screened the titles and abstracts. Differences were resolved by discussion with a third investigator (R.C.). We included all RCTs comparing carfilzomib-based regimens with non-carfilzomib-based regimens in MM. The study selection process is summarised in Appendix S2. Risk of bias was assessed using the Cochrane Collaboration Tool. The primary outcome of our present study was the relative risk of serious infections with carfilzomib, and the relevant data were obtained from ClinicalTrials.gov. Serious infections were defined as infections that were life-threatening or resulted in death, inpatient hospitalisation, extended hospital stay, or significant incapacity in patients. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using the random effects model by Der Simonian and Laird. The heterogeneity across studies was quantified using I statistic. Publication bias was assessed with the Egger’s regression test. All statistical analyses were performed with the Review Manager (RevMan, version 5.3; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Four RCTs with 2954 patients (1486 in the carfilzomib arm and 1468 in the control arm) were included in the final analysis. The characteristics of the included studies are summarised in Table I. The risk of bias amongst studies is given in Appendix S3. Three studies were conducted in patients with relapsed/refractory MM, whereas one study (CLARION) was done in individuals with newly diagnosed MM. The median duration of treatment in the carfilzomib arm ranged from 16 to 88 weeks. Carfilzomib was administered twice weekly in all trials, with a starting dose of 20 mg/ m. The peak doses ranged from 27 to 56 mg/m. A total of 514 serious infection events were noted in patients on carfilzomib-based regimens, compared to 354 in the control arms. The relative risk of total serious infections was significantly elevated with carfilzomib-based regimens (pooled RR 1 40, 95% CI 1 17–1 69; P = 0 0003, Fig 1A). In the carfilzomib arm, 65% of all serious infections involved the respiratory tract, and 38% were pneumonia. Patients on carfilzomib were at a statistically significant higher risk of serious respiratory tract infections (RTIs) than controls (pooled RR 1 30, 95% CI 1 12–1 50; P = 0 0004, Fig 1B). However, there was no significant difference in the incidence of serious pneumonia between the carfilzomib and control groups (pooled RR 1 14, 95% CI 0 92–1 41; P = 0 23). Substantial heterogeneity (I = 57%) was noted across trials. A subgroup analysis based on carfilzomib dose (≤27 vs. >27 mg/m) and treatment setting (relapsed/refractory vs. newly diagnosed) did not reveal any statistically significant subgroup effect. There was no publication bias, and sensitivity analysis did not yield any significant change in our findings. Our meta-analysis found that carfilzomib-based regimens were associated with a significantly higher risk of serious infections, particularly serious RTIs; however, the risk of serious pneumonia was not significantly increased. Despite the tremendous advancement in therapeutics in the last few decades, MM remains an incurable disease with a high rate of relapses and most patients die from disease progression. Infection is an important cause of morbidity and mortality in myeloma, and about half of early deaths are attributable to infections. Risk factors include several host-related, diseaseassociated immune defects, and treatment-related AEs. Patients with MM have significantly decreased numbers of na€ıve or activated CD-8 positive T cells and natural killer cells compared with age-matched healthy individuals. These T-cell subsets decline even more with each successive line of conventional chemotherapy. Proteasome inhibition leads to disruption of intracellular antigen presentation and depletion of alloreactive T cells. Treatment with a PI poses a higher risk of reactivation of viral infection and the development of other opportunistic infections. Prior studies with carfilzomib have reported incidence rates of RTI ranging from 10% to 18 8%. Pneumonia seems to be the most common respiratory AE and correspondence